Analogues of glucose-dependent insulinotropic polypeptide

ABSTRACT

A series of glucose-dependent insulinotropic polypeptide analog compounds, pharmaceutical compositions, and the use of the GIP polypeptide analog compounds as GIP-receptor agonists or antagonists for the treatment of GIP-receptor mediated conditions, such as non-insulin dependent diabetes mellitus and obesity.

This application is a United States national stage filing under 35U.S.C. §371 of international (PCT) application no. PCT/US2009/004552,filed Aug. 7, 2009, and designating the US, which claims priority toU.S. provisional application nos. 61/188,191, filed Aug. 7, 2008, and61/200,629, filed Dec. 2, 2008.

FIELD OF THE INVENTION

The present invention relates to the area of novel analogues ofglucose-dependent insulinotropic polypeptide compounds, pharmaceuticalcompositions containing said compounds, and the use of said compounds asGIP-receptor agonists or antagonists for treatment of GIP-receptormediated conditions, such as non-insulin dependent diabetes mellitus andobesity.

BACKGROUND ART

Glucose-dependent insulinotropic polypeptide (“GIP”, also known as“gastric inhibitory polypeptide”; SEQ ID NO:1) is a 42-residue peptidesecreted by enteroendorine K-cells of the small intestine into thebloodstream in response to oral nutrient ingestion. GIP inhibits thesecretion of gastric acid, and it has been shown to be a potentstimulant for the secretion of insulin from pancreatic beta cells afteroral glucose ingestion (the “incretin effect”) (Creutzfeldt, W., et al.,1979, Diabetologia, 16:75-85).

Insulin release induced by the ingestion of glucose and other nutrientsis due to both hormonal and neural factors (Creutzfeldt, W., et al.,1985, Diabetologia, 28:565-573). Several gastrointestinal regulatorypeptides have been proposed as incretins, and among these candidates,only GIP and glucagon-like peptide 1 (“GLP-1”) appear to fulfill therequirements to be considered physiological stimulants of postprandialinsulin release (Nauck, et al., 1989, J. Clin. Endorinol. Metab.,69:654-662). It has been shown that the combined effects of GIP andGLP-1 are sufficient to explain the full incretin effect of theenteroinsular axis (Fehmann, H. C., et al., 1989, FEBS Lett.,252:109-112).

As is well known to those skilled in the art, the known and potentialuses of GIP are varied and multitudinous. Thus, the administration ofthe compounds of this invention for purposes of eliciting an agonisteffect can have the same effects and uses as GIP itself. These varieduses of GIP may be summarized as follows: treating a disease selectedfrom the group consisting of type 1 diabetes, type 2 diabetes (Visboll,T., 2004, Dan. Med. Bull., 51:364-70), insulin resistance (WO2005/082928), obesity (Green, B. D., et al., 2004, CurrentPharmaceutical Design, 10:3651-3662), metabolic disorder (Gault, V. A.,et al., 2003, Biochem. Biophys. Res. Commun., 308:207-213), centralnervous system disease, neurodegenerative disease, congestive heartfailure, hypoglycemia, and disorders wherein the reduction of foodintake and weight loss are desired. In pancreatic islets, GIP not onlyenhances insulin secretion acutely, but it also stimulates insulinproduction through enhancement of proinsulin transcription andtranslation (Wang, et al., 1996, Mol. Cell. Endocrinol., 116:81-87) andenhances the growth and survival of pancreatic beta cells (Trumper, etal., 2003, Diabetes, 52:741-750). In addition to effects on the pancreasto enhance insulin secretion, GIP also has effects on insulin targettissues directly to lower plasma glucose: enhancement of glucose uptakein adipose (Eckel, et al., 1979, Diabetes, 28:1141-1142) and muscle(O'Harte, et al., 1998, J. Endocrinol., 156:237-243), and inhibition ofhepatic glucose production (Elahi, D., et al., 1986, Can. J. Physiol.Pharmacol., 65:A18).

In addition, a GIP receptor antagonist in accordance with the presentinvention inhibits, blocks or reduces glucose absorption from theintestine of an animal. In accordance with this observation, therapeuticcompositions containing GIP antagonists may be used in patients withnon-insulin dependent diabetes mellitus to improve tolerance to oralglucose in mammals, such as humans, to prevent, inhibit or reduceobesity by inhibiting, blocking or reducing glucose absorption from theintestine of the mammal.

The use of unmodified GIP as a therapeutic, however, is limited by theshort in vivo half-life of about 2 minutes (Said and Mutt, 1970,Science, 169:1217-1218). In serum, both incretins, GIP and GLP-1, aredegraded by dipeptidyl peptidase IV (“DPPIV”). Improving the stabilityof GIP to proteolysis not only maintains the activity of GIP at itsreceptor but, more importantly, prevents the production of GIPfragments, some of which act as GIP receptor antagonists (Gault, et al.,2002, J. Endocrinol., 175:525-533). Reported modifications have includedprotection of the N-terminus of GIP from proteolysis by DPPIV throughmodification of the N-terminal tyrosine (O'Harte, et al., 2002,Diabetologia, 45:1281-1291), mutation of the alanine at position 2(Hinke, et al., 2002, Diabetes, 51:656-661), mutation of glutamic acidat position 3 (Gault, et al., 2003, Biochem. Biophys. Res. Commun.,308:207-213), and mutation of alanine at position 13 (Gault, et al.,2003, Cell Biol. International, 27:41-46),

The following patent applications have been filed related to the effectsof GIP analogues on the function of various target organs and theirpotential use as therapeutic agents:

PCT publication WO 00/58360 discloses peptidyl analogues of GIP whichstimulate the release of insulin. In particular, this applicationdiscloses specific peptidyl analogues comprising at least 15 amino acidresidues from the N-terminal end of GIP(1-42), e.g., an analogue of GIPcontaining exactly one amino acid substitution or modification atpositions 1, 2 and 3, such as [Pro³]GIP(1-42).

PCT publication WO 98/24464 discloses an antagonist of GIP consistingessentially of a 24-amino acid polypeptide corresponding to positions7-30 of the sequence of GIP, a method of treating non-insulin dependentdiabetes mellitus and a method of improving glucose tolerance in anon-insulin dependent diabetes mellitus patient.

PCT publication WO 03/082898 discloses C-terminal truncated fragmentsand N-terminal modified analogues of GIP, as well as various GIPanalogues with a reduced peptide bond or alterations of the amino acidsclose to the DPPIV-specific cleavage site. This application furtherdiscloses analogues with different linkers between potential receptorbinding sites of GIP. The compounds of this application are alleged tobe useful in treating GIP-receptor mediated conditions, such asnon-insulin dependent diabetes mellitus and obesity.

There exists a need for improved analogues of GIP, which are stable informulation and have long plasma half-life in vivo resulting fromdecreased susceptibility to proteolysis and decreased clearance whilemaintaining binding affinity to a GIP receptor to elicit respectiveagonistic or antagonistic effects. Moreover, among other therapeuticeffects of the compounds of the present invention as illustrated herein,tighter control of plasma glucose levels may prevent long-term diabeticcomplications, thereby providing an improved quality of life forpatients.

SUMMARY OF THE INVENTION

In one aspect, the invention relates to peptide variants of GIP of thefollowing formula (I):(R²R³)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-A³⁹-A⁴⁰-A⁴¹-A⁴²-A⁴³-R¹,  (I)wherein:

A¹ is Tyr, N-Me-Tyr, 4Hppa, Orn(N—C(O)—(CH₂)₁₂—CH₃) orHN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O);

A² is Ala, Abu, D-Abu, Acc, Aib, β-Ala, D-Ala, Gaba, Gly, Ser, D-Ser,Thr, D-Thr, Val, or D-Val;

A³ is Glu, Aib, Asp, NMe-Asp, Dhp, Dmt, Glu, NMe-Glu, 3Hyp, 4Hyp, 4Ktp,Pro, hPro, Thz, or Tic;

A⁴ is Gly, Acc, Aib, or β-Ala;

A⁵ is Thr, Acc, Aib, or Ser;

A⁶ is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Trp;

A⁷ is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;

A⁸ is Ser, Aib, or Thr;

A⁹ is Asp, Aib, or Glu;

A¹⁰ is Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or(X⁴,X⁵,X⁶,X⁷,X⁸)Phe;

A¹¹ is Ser, Acc, Aib, Nle, or Thr;

A¹² is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;

A¹³ is Ala, Acc, Aib, β-Ala, D-Ala, Gly, or Ser;

A¹⁴ is Met, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, Phe, Tle, or Val;

A¹⁵ is Asp, Aib, or Glu;

A¹⁶ is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), orPen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃);

A¹⁷ is Ile, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val;

A¹⁸ is His, Amp, Arg, 2-Pal, 3-Pal, 4-Pal, Phe, or Tyr;

A¹⁹ is Gln, Aib, or Asn;

A²⁰ is Gln, Aib, or Asn;

A²¹ is Asp, Aib, or Glu;

A²² is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Trp;

A²³ is Val, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, or Tle;

A²⁴ is Asn, Aib, or Gln;

A²⁵ is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or(X⁴,X⁵,X⁶,X⁷,X⁸)Phe;

A²⁶ is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Tle;

A²⁷ is Leu, Acc, Aib, Cha, Ile, Nle, Phe, (X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Tle;

A²⁸ is Ala, Acc, or Aib;

A²⁹ is Gln, Aib, Asn, or deleted;

A³⁰ is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³¹ is Gly, Acc, Aib, β-Ala, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), His,Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³² is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³³ is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³⁴ is Asn, Aib, Gln, Ser, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³⁵ is Asp, Aib, Glu, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³⁶ is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³⁷ is Lys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵)—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³⁸ is His, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr,HN—CH((CH₂)_(n)—N(R⁴R⁵)—C(O), Cys(succinimide-N-alkyl),hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A³⁹ is Asn, Aib, Gln, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A⁴⁰ is Ile, Acc, Aib, Ser, Thr, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A⁴¹ is Thr, Acc, Aib, Asn, Gln, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A⁴² is Gln, Acc, Aib, Asn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

A⁴³ is Acc, Aib, Ala, Asp, Gln, His, Phe, Thr, Trp,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), Cys(succinimide-N-alkyl),hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted;

R¹ is OH, NH₂, (C₁-C₃₀)alkoxy, or NH—X²—CH₂—Z⁰, wherein X² is a (C₀-C₃₀)hydrocarbon moiety and Z⁰ is H, OH, CO₂H, or CONH₂;

each of R², R³, R⁴ and R⁵ is independently selected from the groupconsisting of H, (C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl,(C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl,substituted (C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₁-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl,substituted aryl(C₁-C₃₀)alkyl, and substituted aryl(C₁-C₃₀)acyl;provided that when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted(C₁-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is H,(C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted(C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl; further provided thatwhen R⁴ is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)acyl, orsubstituted aryl(C₁-C₃₀)acyl, then R⁵ is H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted(C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl;

n is, independently for each occurrence, an integer from 1 to 5inclusive;

s, t, x and y each is, independently for each occurrence, an integerfrom 1 to 30 inclusive;

X⁴, X⁵, X⁶, X² and X⁸ each is, independently for each occurrence, H, F,Cl, Br, I, (C₁₋₁₀)alkyl, substituted (C₁₋₁₀)alkyl, aryl, substitutedaryl, OH, NH₂, NO₂, or CN;

provided that when A¹ is 4Hppa, then R² and R³ are deleted;

further provided that only one amino acid at positions 1, 2 or 3 of thecompound is substituted or modified; and

further provided that the compound of formula (I) is not(D-Ala²)hGIP(1-42), (Pro³)hGIP(1-42) (SEQ ID NO:120), (Aib³)hGIP(1-42)(SEQ ID NO:121), (Ser²)hGIP(1-42) (SEQ ID NO:122), (Abu²)hGIP(1-42) (SEQID NO: 123), (D-Abu²)hGIP(1-42), (D-Ser²)hGIP(1-42), (D-Thr²)hGIP(1-42),or (D-Val²)hGIP(1-42).

A subset (A) of the compounds covered by the above formula (I) are thosein which:

A¹ is Tyr, N-Me-Tyr, 4Hppa, or Orn(N—C(O)—(CH₂)₁₂—CH₃);

A² is Ala, A5c, A6c, Aib, D-Ala, Gly, or Ser;

A³ is Glu, Dhp, 3Hyp, 4Hyp, Pro, hPro, or Tic;

A⁴ is Gly or Aib;

A⁵ is Thr, A5c, or Aib;

A⁶ is Phe or A6c;

A⁷ is Ile, A5c, A6c, or Aib;

A⁸ is Ser or Aib;

A⁹ is Asp or Aib;

A¹⁰ is Tyr;

A¹¹ is Ser, A5c, A6c, Aib, or Nle;

A¹² is Ile, A5c, or Aib;

A¹³ is Ala or Aib;

A¹⁴ is Met, A5c, A6c, or Nle;

A¹⁵ is Asp;

A¹⁶ is Lys;

A¹⁷ is Ile or A6c;

A¹⁸ is His;

A¹⁹ is Gln;

A²⁰ is Gln;

A²¹ is Asp;

A²² is Phe;

A²³ is Val;

A²⁴ is Asn;

A²⁵ is Trp;

A²⁶ is Leu or A6c;

A²⁷ is Leu or A6c;

A²⁸ is Ala or Aib;

A²⁹ is Gln;

A³⁰ is Lys;

A³¹ is Gly, Aib, Cys(Psu), His, or deleted;

A³² is Lys, Cys(Psu), or deleted;

A³³ is Lys, Cys(Psu), or deleted;

A³⁴ is Asn, Cys(Psu), or deleted;

A³⁵ is Asp, Cys(Psu), or deleted;

A³⁶ is Trp, Cys(Psu), or deleted;

A³⁷ is Lys, Cys(Psu), or deleted;

A³⁸ is His, Cys(Psu), or deleted;

A³⁹ is Asn, Cys(Psu), or deleted;

A⁴⁰ is Ile, A5c, A6c, Cys(Psu), or deleted;

A⁴¹ is Thr, A5c, A6c, Aib, Cys(Psu), or deleted;

A⁴² is Gln or deleted;

A⁴³ is Cys(Psu), Gln, His, or deleted; and

provided that the compound contains at least one additional amino acidsubstitution or modification at positions 4-43.

A subset of the compounds of the preceding subset (A) are those in whichA² is D-Ala.

Another subset of the compounds of the preceding subset (A) are those inwhich A³¹ to A⁴³ are deleted.

Another subset of the compounds of the preceding subset (A) are those inwhich A² is Ala, A5c, A6c, or Gly; and A³ is Glu, Dhp, 3Hyp, 4Hyp, hPro,or Tic.

Another aspect of the present invention encompasses compounds consistingessentially of a sequence of the first 30 consecutive amino acidresidues from the N-terminal end of the native hGIP amino acid sequence,wherein the sequence comprises A5c, A6c, Aib, D-Ala, Gly or Sersubstitution at position 2, and at least one additional amino acidsubstitution or modification at positions 3-30.

A subset of the compounds of the immediately preceding aspect of thepresent invention are those in which A² is Aib; A³ is Pro; and at leastone of A⁷, A¹¹, A¹³ and A¹⁴ is not the amino acid residue of thecorresponding position in the native GIP.

Yet another aspect of the present invention encompasses GIP analoguescomprising A5c, A6c, Aib, D-Ala, Gly or Ser substitution at position 2,and at least one additional amino acid substitution or modification atpositions 1 and 3-42.

A subset of the compounds of the immediately preceding aspect of thepresent invention are those in which A² is Aib.

Preferred compounds of formula (I) are:

-   Example 1: (Aib^(2, 11))hGIP(1-42)-OH (SEQ ID NO:4);-   Example 2: (Aib^(2, 9))hGIP(1-42)-OH (SEQ ID NO:5);-   Example 3: (Aib^(2, 7))hGIP(1-42)-OH (SEQ ID NO:6);-   Example 4: (Aib^(2, 5))hGIP(1-42)-OH (SEQ ID NO:7);-   Example 5: (Aib², A5c⁵)hGIP(1-42)-OH (SEQ ID NO:8);-   Example 6: (Aib², A5c⁷)hGIP(1-42)-OH (SEQ ID NO:9);-   Example 7: (Aib², A5c¹²)hGIP(1-42)-OH (SEQ ID NO:10);-   Example 8: (Aib^(2, 12))hGIP(1-42)-OH (SEQ ID NO:11);-   Example 9: (Aib^(2, 8))hGIP(1-42)-OH (SEQ ID NO:12);-   Example 10: (Aib^(2, 4))hGIP(1-42)-OH (SEQ ID NO:13);-   Example 11: (Aib², A5c⁵)hGIP(1-30)-NH₂ (SEQ ID NO:14);-   Example 12: (Aib², A5c⁷)hGIP(1-30)-NH₂ (SEQ ID NO:15);-   Example 13: (Aib², A5c¹²)hGIP(1-30)-NH₂ (SEQ ID NO:16);-   Example 14: (Aib^(2, 4))hGIP(1-30)-NH₂ (SEQ ID NO:17);-   Example 15: (Aib^(2, 5))hGIP(1-30)-NH₂ (SEQ ID NO:18);-   Example 16: (Aib^(2, 7))hGIP(1-30)-NH₂ (SEQ ID NO:19);-   Example 17: (Aib^(2, 8))hGIP(1-30)-NH₂ (SEQ ID NO:20);-   Example 18: (Aib^(2, 9))hGIP(1-30)-NH₂ (SEQ ID NO:21);-   Example 19: (Aib^(2, 11))hGIP(1-30)-NH₂ (SEQ ID NO:22);-   Example 20: (Aib^(2, 12))hGIP(1-30)-NH₂ (SEQ ID NO:23);-   Example 21: (Aib^(2, 13), A6c⁷, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:24);-   Example 22: (Aib^(2, 31), A6c⁷)hGIP(1-42)-OH (SEQ ED NO:25);-   Example 23: (Aib^(2, 41), A6c⁷)hGIP(1-42)-OH (SEQ ID NO:26);-   Example 24: (Aib^(2, 31), A6c⁷, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:27);-   Example 25: (Aib^(2, 41), A6c⁷, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:28);-   Example 26: (Aib², A6c^(7, 26), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:29);-   Example 27: (Aib², A6c^(7, 27), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:30);-   Example 28: (Aib², A6c^(7, 40), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:31);-   Example 29: (Aib², A6c^(7, 41), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:32);-   Example 30: (Aib^(2, 28), A6c⁷, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:33);-   Example 31: (Aib², A6c⁷, Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:34);-   Example 32: (Aib², A5c⁷, Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:35);-   Example 33: (Aib^(2, 11), Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:36);-   Example 34: (A5c^(2, 7), Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:37);-   Example 35: (Aib², A5c^(7, 14))hGIP(1-30)-NH₂ (SEQ ID NO:38);-   Example 36: (A6c^(2, 7), Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:39);-   Example 37: (Aib², A6c^(7, 17), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:40);-   Example 38: (Aib^(2, 11), A6c¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:41);-   Example 39: (Aib², A6c^(7, 14))hGIP(1-30)-NH₂ (SEQ ID NO:42);-   Example 40: (A5c², Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:43);-   Example 41: (Aib^(2, 11), A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:44);-   Example 42: (Aib², A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:45);-   Example 43: (Aib², A6c⁷)hGIP(1-42)-OH (SEQ ID NO:46);-   Example 44: (Aib², A5c⁷, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:47);-   Example 45: (Aib^(2, 11), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:48);-   Example 46: (Aib², A5c¹¹)hGIP(1-30)-NH₂ (SEQ ID NO:49);-   Example 47: (Aib^(2, 13))hGIP(1-30)-NH₂ (SEQ ID NO:50);-   Example 48: (Aib², A5c¹¹, A6c¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:51);-   Example 49: (Aib^(2, 13), Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:52);-   Example 50: (Aib², A5c¹¹, Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:53);-   Example 51: (Aib², A6c^(7, 14))hGIP(1-42)-OH (SEQ ID NO:54);-   Example 52: (Aib², A6c⁷)hGIP(1-30)-NH₂ (SEQ ID NO:55);-   Example 53: (Aib², A5c¹¹)hGIP(1-42)-OH (SEQ ID NO:56);-   Example 54: (Aib², A5c¹¹, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:57);-   Example 55: (Aib², A6c⁷, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:58);-   Example 56: (A5c^(2, 7), A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:59);-   Example 57: (Aib^(2, 13), Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:60);-   Example 58: (Aib², A5c⁷, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:61);-   Example 59: (Aib², A5c^(7, 14))hGIP(1-42)-OH (SEQ ID NO:62);-   Example 60: (Aib^(2, 13))hGIP(1-42)-OH (SEQ ID NO:63);-   Example 61: (Aib², A5c¹¹, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:64);-   Example 62: (Pro³, Aib¹³, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:65);-   Example 63: (hPro³, Aib¹³, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:66);-   Example 64: (Dhp³, Aib¹³, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:67);-   Example 65: (hPro³, Aib¹³)hGIP(1-42)-OH (SEQ ID NO:68);-   Example 66: (Tic³, Aib¹³)hGIP(1-42)-OH (SEQ ID NO:69);-   Example 67: (4Hyp³, Aib¹³)hGIP(1-42)-OH (SEQ ID NO:70);-   Example 68: (4Hyp³, Aib¹³, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:71);-   Example 69: (Tic³, Aib¹³, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:72);-   Example 70: (3Hyp³, Aib¹³, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:73);-   Example 71: (Tic³, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:74);-   Example 72: (hPro³, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:75);-   Example 73: [Aib², A6c⁷, Cys(Psu)⁴¹]hGIP(1-42)-OH (SEQ ID NO:76);-   Example 74: (hPro³, A5c¹¹)hGIP(1-42)-OH (SEQ ID NO:77);-   Example 75: (Pro³, Aib¹³)hGIP(1-42)-OH (SEQ ID NO:78);-   Example 76: (Pro³, A5c^(7, 14))hGIP(1-42)-OH (SEQ ID NO:79);-   Example 77: (Pro³, A5c¹¹)hGIP(1-42)-OH (SEQ ID NO:80);-   Example 78: [Aib², A6c⁷, Cys(Psu)⁴⁰]hGIP(1-42)-OH (SEQ ID NO:81);-   Example 79: [Aib², A6c⁷, Cys(Psu)³⁹]hGIP(1-42)-OH (SEQ ID NO:82);-   Example 80: [Aib², A6c⁷, Cys(Psu)³⁸]hGIP(1-42)-OH (SEQ ID NO:83);-   Example 81: [Aib², A6c⁷, Cys(Psu)³⁶]hGIP(1-42)-OH (SEQ ID NO:84);-   Example 82: (Tic³, A5c¹¹)hGIP(1-42)-OH (SEQ ID NO:85);-   Example 83: (hPro³, A5c¹¹, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:86);-   Example 84: (4Hyp³, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:87);-   Example 85: [Aib², A6c⁷, Cys(Psu)³⁵]hGIP(1-42)-OH (SEQ ID NO:88);-   Example 86: [Aib², A6c⁷, Cys(Psu)³⁴]hGIP(1-42)-OH (SEQ ID NO:89);-   Example 87: (4Hyp³, A5c¹¹)hGIP(1-42)-OH (SEQ ID NO:90);-   Example 88: (4Hyp³, A5c¹¹, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:91);-   Example 89: (Tic³, A5c¹¹, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:92);-   Example 90: [Aib², A6c⁷, Cys(Psu)³¹]hGIP(1-42)-OH (SEQ ID NO:93);-   Example 91: (Pro³, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:94);-   Example 92: (Pro³, A5c¹¹, Nle¹⁴)hGIP(1-30)-OH (SEQ ID NO:95);-   Example 93: (Aib², A6c⁷, Gln⁴³)hGIP(1-43)-OH (SEQ ID NO:96);-   Example 94: [Aib², A6c⁷, Cys(Psu)³²]hGIP(1-42)-OH (SEQ ID NO:97);-   Example 95: [Aib², A6c⁷, Cys(Psu)⁴³]hGIP(1-43)-OH (SEQ ID NO:98);-   Example 96: (Pro³, A5c¹¹, A6c¹⁴)hGIP(1-30)-NH₂ (SEQ ID NO:99);-   Example 97: (Pro³, A6c⁷)hGIP(1-30)-NH₂ (SEQ ID NO:100);-   Example 98: (Pro³, A5c¹¹)hGIP(1-30)-NH₂ (SEQ ID NO:101);-   Example 99: [Aib², A6c⁷, Cys(Psu)³³]hGIP(1-42)-OH (SEQ ID NO:102);-   Example 100: [Aib², A6c⁷, Cys(Psu)³⁷]hGIP(1-42)-OH (SEQ ID NO:103);-   Example 101: (4Hppa¹, Aib¹³)hGIP(1-42)-OH (SEQ ID NO:104);-   Example 102: (Pro³, A5c¹¹, A6c¹⁴)hGIP(1-42)-OH (SEQ ID NO:105);-   Example 103: [Orn¹(N—C(O)—(CH₂)₁₂—CH₃), A6c⁷]hGIP(1-42)-OH (SEQ ID    NO:106);-   Example 104: (D-Ala², A5c^(11,40))hGIP(1-42)-OH;-   Example 105: (D-Ala², A5c¹¹, His⁴³)hGIP(1-43)-OH;-   Example 106: (D-Ala², A5c^(11, 41))hGIP(1-42)-OH;-   Example 107: (D-Ala², A6c^(11, 14, 41))hGIP(1-42)-OH;-   Example 108: (Aib^(2, 13), Pro³, Nle¹⁴)hGIP(1-30)-NH₂ (SEQ ID    NO:107);-   Example 109: (Aib², Pro³, A6c⁷)hGIP(1-30)-NH₂ (SEQ ID NO:108);-   Example 110: (Aib², Pro³, A5c¹¹)hGIP(1-30)-NH₂ (SEQ ID NO:109);-   Example 111: (Aib², Pro³, A5c¹¹, Nle¹⁴)hGIP(1-30)-NH₂(SEQ ID    NO:110);-   Example 112: (Aib², Pro³, A5c¹¹, A6c¹⁴)hGIP(1-30)-NH₂ (SEQ ID    NO:111);-   Example 113: (NMe-Tyr¹, Aib², A5c¹¹, Nle¹⁴)hGIP(1-42)-OH (SEQ ID    NO:112);-   Example 114: (Gly², A6c^(11, 14, 41))hGIP(1-42)-OH (SEQ ID NO:113);-   Example 115: (Gly², Aib¹³, A5c⁴⁰)hGIP(1-42)-OH (SEQ ID NO:114);-   Example 116: (Gly², A5c^(11, 41))hGIP(1-42)-OH (SEQ ID NO:115);-   Example 117: (Gly², A5c¹¹, His⁴³)hGIP(1-43)-OH (SEQ ID NO:116);-   Example 118: (Gly², A5c¹¹, Nle¹⁴, His⁴³)hGIP(1-43)-OH (SEQ ID    NO:117);-   Example 119: (D-Ala², A5c¹¹, Nle¹⁴, His⁴³)hGIP(1-43)-OH;-   Example 120: (D-Ala², A5c^(11, 14), His⁴³)hGIP(1-43)-OH;-   Example 121: (D-Ala², A5c^(11, 14))hGIP(1-30)-NH₂;-   Example 122: (D-Ala², A5c¹¹, His³¹)hGIP(1-31)-NH₂; and-   Example 123: (Aib², A5c^(11,14), His⁴³)hGIP(1-43)-OH (SEQ ID    NO:118).

According to another aspect of the present invention, a compoundaccording to the present invention as summarized hereinabove and claimedin the appended claims may further comprise a covalently linked PEGmoiety, in which said PEG moiety is covalently linked to the compoundvia a Cys(maleimide), hCys(maleimide), or Pen(maleimide) linker, to formCys(succinimide-N-PEG), hCys(succinimide-N-PEG), orPen(succinimide-N-PEG), wherein “succinimide-N-PEG” is either linear orbranched as defined hereinbelow. Such PEG moiety has average molecularweight of from about 2,000 to about 80,000, and preferably such PEGmoiety is selected from the group consisting of 5K PEG, 10K PEG, 20KPEG, 30K PEG, 40K PEG, 50K PEG, and 60K PEG, to formCys(succinimide-N-5K PEG), Cys(succinimide-N-10K PEG),Cys(succinimide-N-20K PEG), Cys(succinimide-N-30K PEG),Cys(succinimide-N-40K PEG), Cys(succinimide-N-50K PEG),Cys(succinimide-N-60K PEG), hCys(succinimide-N-5K PEG),hCys(succinimide-N-10K PEG), hCys(succinimide-N-20K PEG),hCys(succinimide-N-30K PEG), hCys(succinimide-N-40K PEG),hCys(succinimide-N-50K PEG), hCys(succinimide-N-60K PEG),Pen(succinimide-N-5K PEG), Pen(succinimide-N-10K PEG),Pen(succinimide-N-20K PEG), Pen(succinimide-N-30K PEG),Pen(succinimide-N-40K PEG), Pen(succinimide-N-50K PEG), orPen(succinimide-N-60K PEG).

PEGylation occurs at any one of amino acid residue positions 16, 30, and31-43, and preferably at any one of amino acid residue positions 32, 33and 43, whereby Cys(succinimide-N-PEG), hCys(succinimide-N-PEG), orPen(succinimide-N-PEG) is placed in any one of such amino acid residuepositions.

Further, the above formula (I) may be expanded to provide PEGylationsites at positions A⁴⁴-A⁴⁷. The C-terminus of such PEGylated compoundsof the present invention may be amidated, e.g., (Aib^(2, 11))hGIP(1-42)-NH₂ (SEQ ID NO:119), or it may remain as free acid, e.g.,(Aib^(2, 11))hGIP(1-42)-OH (SEQ ID NO:4).

DETAILED DESCRIPTION OF THE INVENTION

The application employs the following commonly understood abbreviations:

Abu: α-aminobutyric acid

Acc: 1-amino-1-cyclo(C₃-C₉)alkyl carboxylic acid

-   -   A3c: 1-amino-1-cyclopropanecarboxylic acid    -   A4c: 1-amino-1-cyclobutanecarboxylic acid    -   A5c: 1-amino-1-cyclopentanecarboxylic acid    -   A6c: 1-amino-1-cyclohexanecarboxylic acid

Act: 4-amino-4-carboxytetrahydropyran

Ado: 12-aminododecanoic acid

Aib: α-aminoisobutyric acid

Aic: 2-aminoindan-2-carboxylic acid

Ala or A: alanine

β-Ala: beta-alanine

Amp: 4-amino-phenylalanine;

Apc: 4-amino-4-carboxypiperidine:

Arg or R: arginine

hArg: homoarginine

Asn or N: asparagine

Asp or D: aspartic acid

Aun: 11-aminoundecanoic acid

Ava: 5-aminovaleric acid

Cha: β-cyclohexylalanine

Cys or C: cysteine

Dhp: 3,4-dehydroproline

Dmt: 5,5-dimethylthiazolidine-4-carboxylic acid

Gaba: γ-aminobutyric acid

Gln or Q: glutamine

Glu or E: glutamic acid

Gly or G: glycine

His or H: histidine

4Hppa: 3-(4-hydroxyphenyl)propionic acid

3Hyp: 3-hydroxyproline

4Hyp: 4-hydroxyproline

hPro: homoproline

Ile or I: isoleucine

4Ktp: 4-ketoproline

Leu or L: leucine

Lys or K: lysine

Met or M: methionine

Nle: norleucine

NMe-Tyr: N-methyl-tyrosine

1Nal or 1-Nal: β-(1-naphthyl)alanine

2Nal or 2-Nal: β-(2-naphthyl)alanine

Nle: norleucine

Nva: norvaline

Orn: ornithine

2Pal or 2-Pal: β-(2-pyridinypalanine

3Pal or 3-Pal: β-(3-pyridinypalanine

4Pal or 4-Pal: β-(4-pyridinypalanine

Pen: penicillamine

Phe or F: phenylalanine

(3,4,5F)Phe: 3,4,5-trifluorophenylalanine

(2,3,4,5,6)Phe: 2,3,4,5,6-pentafluorophenylalanine

Pro or P: proline

Psu: N-propylsuccinimide

Ser or S: serine

Taz: β-(4-thiazolypalanine

3Thi: β-(3-thienyl)alanine

Thr or T: threonine

Thz: thioproline

Tic: tetrahydroisoquinoline-3-carboxylic acid

Tle: tert-leucine

Trp or W: tryptophan

Tyr or Y: tyrosine

Val or V: valine

Certain other abbreviations used herein are defined as follows:

Acn: acetonitrile

Boc: tert-butyloxycarbonyl

BSA: bovine serum albumin

DCM: dichloromethane

DIPEA: diisopropylethyl amine

DMF: dimethylformamide

ESI: electrospray ionization

Fmoc: 9-fluorenylmethyloxycarbonyl

HBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

HOBt: 1-hydroxy-benzotriazole

HPLC: high performance liquid chromatography

IBMX: isobutylmethylxanthine

LC-MS: liquid chromatography-mass spectrometry

Mtt: methyltrityl

NMP: N-methylpyrrolidone

5K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about5,000

10K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about10,000

20K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about20,000

30K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about30,000

40K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about40,000

50K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about50,000

60K PEG: polyethylene glycol, which may include other functional groupsor moieties such as a linker, and which is either linear or branched asdefined hereinbelow, with an average total molecular weight of about60,000

tBu: tert-butyl

TIS: triisopropylsilane

Trt: trityl

TFA: trifluoro acetic acid

Z: benzyloxycarbonyl

“Cys(succinimide-N-alkyl)” has the structure of:

“Cys(Psu)” has the structure of:

“Orn(N—C(O)—(CH₂)₁₂—CH₃)” has the structure of:

“Cys(succinimide-N—(CH₂)x-C(O)—NH—(CH₂)y-CH₃)” has the structure of:

wherein, x=1-30, and y=1-30.

“hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃)” has the structureof:

wherein, x=1-30, and y=1-30.

“Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃)” has the structureof:

wherein, x=1-30, and y=1-30.

“Cys(succinimide-N—(CH₂)_(s)NH—C(O)—(CH₂)_(t)—CH₃)” has the structureof:

wherein, s=1-30, and t=1-30.

“hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃)” has the structureof:

wherein s=1-30, and t=1-30.

“Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃)” has the structureof:

wherein s=1-30, and t=1-30.

“Cys(succinimide-N-PEG)” has the structure of:

“hCys(succinimide-N-PEG)” has the structure of:

“Pen(succinimide-N-PEG)” has the structure of:

“Cys(succinimide-N—(CH₂)₂—C(O)NH—(CH₂)₃-PEG)” has the structure of:

“Cys(succinimide-N—(CH₂)₂—C(O)NH—(CH₂)₃—O—CH₂—CH(PEG)-CH₂-PEG)” has thestructure of:

With the exception of the N-terminal amino acid, all abbreviations(e.g., Ala) of amino acids in this disclosure stand for the structure of—NH—C(R)(R′)—CO—, wherein R and R′ each is, independently, hydrogen orthe side chain of an amino acid (e.g., R═CH₃ and R′═H for Ala), or R andR′ may be joined to form a ring system. For the N-terminal amino acid,the abbreviation stands for the structure of (R²R³)N—C(R)(R′)—CO—,wherein R² and R³ are as defined in the above formula (I).

The term “(C₁-C₃₀)hydrocarbon moiety” encompasses alkyl, alkenyl andalkynyl, and in the case of alkenyl and alkynyl there are C₂-C₃₀.

A peptide of this invention is also denoted herein by another format,e.g., (A5c²)hGIP(1-42)-OH (SEQ ID NO:3), with the substituted aminoacids from the natural sequence placed between the brackets (e.g., A5c²for Ala² in hGIP). The numbers between the parentheses refer to thenumber of amino acids present in the peptide (e.g., hGIP(1-42)-OH (SEQID NO:1) is amino acids 1 through 42 of the peptide sequence for hGIP).The designation “NH₂” in hGIP(1-30)-NH₂ (SEQ ID NO:2) indicates that theC-terminus of the peptide is amidated; hGIP(1-42) (SEQ ID NO:1) orhGIP(1-42)-OH (SEQ ID NO:1) means that the C-terminus is the free acid.

Human GIP (“hGIP”) has the amino acid sequence of:

“Acyl” refers to R″—C(O)—, where R″ is H, alkyl, substituted alkyl,heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl,aryl, alkylaryl, or substituted alkylaryl.

“Alkyl” refers to a hydrocarbon group containing one or more carbonatoms, where multiple carbon atoms if present are joined by singlebonds. The alkyl hydrocarbon group may be straight-chain or contain oneor more branches or cyclic groups.

“Substituted alkyl” refers to an alkyl wherein one or more hydrogenatoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen, (i.e.,fluorine, chlorine, bromine, and iodine), —OH, —CN, —SH, —NH₂, —NHCH₃,—NO₂, —C₁₋₂₀ alkyl substituted with halogens, —CF₃, —OCH₃, —OCF₃, and—(CH₂)₀₋₂₀—COOH. In different embodiments 1, 2, 3 or 4 substituents arepresent. The presence of —(CH₂)₀₋₂₀—COOH results in the production of analkyl acid. Examples of alkyl acids containing, or consisting of,—(CH₂)₀₋₂₀—COOH include 2-norbornane acetic acid, tert-butyric acid and3-cyclopentyl propionic acid.

“Heteroalkyl” refers to an alkyl wherein one of more of the carbon atomsin the hydrocarbon group are replaced with one or more of the followinggroups: amino, amido, —O—, —S— or carbonyl. In different embodiments 1or 2 heteroatoms are present.

“Substituted heteroalkyl” refers to a heteroalkyl wherein one or morehydrogen atoms of the hydrocarbon group are replaced with one or moresubstituents selected from the group consisting of halogen, —OH, —CN,—SH, —NH₂, —NHCH₃, —NO₂, —C₁₋₂₀ alkyl substituted with halogens, —CF₃,—OCH₃, —OCF₃, and —(CH₂)₀₋₂₀—COOH. In different embodiments 1, 2, 3 or 4substituents are present.

“Alkenyl” refers to a hydrocarbon group made up of two or more carbonswherein one or more carbon-carbon double bonds are present. The alkenylhydrocarbon group may be straight-chain or contain one or more branchesor cyclic groups.

“Substituted alkenyl” refers to an alkenyl wherein one or more hydrogensare replaced with one or more substituents selected from the groupconsisting of halogen, —OH, —CN, —SH, —NH₂, —NHCH₃, —NO₂, —C₁₋₂₀ alkylsubstituted with halogens, —CF₃, —OCH₃, —OCF₃, and —(CH₂)₀₋₂₀—COOH. Indifferent embodiments 1, 2, 3 or 4 substituents are present.

“Aryl” refers to an optionally substituted aromatic group with at leastone ring having a conjugated pi-electron system, containing up to threeconjugated or fused ring systems. Aryl includes carbocyclic aryl,heterocyclic aryl and biaryl groups. Preferably, the aryl is a 5 or 6membered ring. Preferred atoms for a heterocyclic aryl are one or moresulfur, oxygen, and/or nitrogen. Examples of aryl include phenyl,1-naphthyl, 2-naphthyl, indole, quinoline, 2-imidazole, and9-anthracene. Aryl substituents are selected from the group consistingof —C₁₋₂₀ alkyl, —C₁₋₂₀ alkoxy, halogen, —OH, —CN, —SH, —NH₂, —NO₂,—C₁₋₂₀ alkyl substituted with halogens, —CF₃, —OCF₃, and—(CH₂)₀₋₂₀—COOH. In different embodiments the aryl contains 0, 1, 2, 3,or 4 substituents.

“Alkylaryl” refers to an “alkyl” joined to an “aryl”.

Synthesis

The peptides of this invention can be prepared by standard solid phasepeptide synthesis. See, e.g., Stewart, J. M., et al., 1984, Solid PhaseSynthesis, Pierce Chemical Co., 2d ed. If R¹ is NH—X²—CH₂—CONH₂, i.e.,Z⁰═CONH₂, the synthesis of the peptide starts with Fmoc-HN—X²—CH₂—CONH₂which is coupled to Rink amide MBHA resin. If R¹ is NH—X²—CH₂—COOH,i.e., Z⁰═COOH, the synthesis of the peptide starts withFmoc-HN—X²—CH₂—COOH which is coupled to Wang resin. For this particularstep, 2 molar equivalents of Fmoc-HN—X²—COOH, HBTU and HOBt and 10 molarequivalents of DIPEA are used. The coupling time is about 8 hours.

In the synthesis of a GIP analogue of this invention containing A5c,A6c, and/or Aib, the coupling time is 2 hrs for these residues and theresidue immediately following them.

The substituents R² and R³ of the above generic formula can be attachedto the free amine of the N-terminal amino acid A¹ by standard methodsknown in the art. For example, alkyl groups, e.g., (C₁-C₃₀)alkyl, can beattached using reductive alkylation. Hydroxyalkyl groups, e.g.,(C₁-C₃₀)hydroxyalkyl, can also be attached using reductive alkylationwherein the free hydroxy group is protected with a tert-butyl ester.Acyl groups, e.g., —C(O)X³, can be attached by coupling the free acid,e.g., —X³COOH, to the free amine of the N-terminal amino acid by mixingthe completed resin with 3 molar equivalents of both the free acid anddiisopropylcarbodiimide in methylene chloride for about one hour. If thefree acid contains a free hydroxy group, e.g.,3-fluoro-4-hydroxyphenylacetic acid, then the coupling should beperformed with an additional 3 molar equivalents of HOBT.

The following examples describe synthetic methods for making a peptideof this invention, which methods are well-known to those skilled in theart. Other methods are also known to those skilled in the art. Theexamples are provided for the purpose of illustration and are not meantto limit the scope of the present invention in any manner.

Example 73 [Aib², A6c⁷, Cys(Psu)⁴¹]hGIP(1-42)-OH

Solid-phase peptide synthesis was used to assemble the peptide usingmicrowave-assisted Fmoc Chemistry on a Liberty Peptide Synthesizer (CEM;Matthews, N.C., USA) at the 0.1 mmole scale. Pre-loadedFmoc-Gln(Trt)-Wang resin (0.59 mmole/g; Novabiochem, San Diego, Calif.,USA) was used to generate the C-terminal acid peptide. The resin (0.17g) was placed in a 50 ml conical tube along with 15 ml ofdimethylformamide (DMF) and loaded onto a resin position on thesynthesizer. The resin was then quantitatively transferred to thereaction vessel via the automated process. The standard Libertysynthesis protocol for 0.1 mmole scale synthesis was used. This protocolinvolved deprotecting the N-terminal Fmoc moiety via an initialtreatment with 7 ml of 20% piperidine, containing 0.1MN-hydroxybenzotriazole (HOBT), in DMF. The initial deprotection step wasfor 30 seconds with microwave power (45 watts, maximum temperature of75° C.), and nitrogen bubbling (3 seconds on/7 seconds off). Thereaction vessel was then drained and a second piperidine treatment,identical to the first treatment, except that it was for a 3-minuteduration. The resin was then drained and thoroughly washed with DMFseveral times. The protected amino acid, Fmoc-Thr(tBu)-OH, prepared as0.2M stock solution in DMF, was then added (2.5 ml, 5 eq.), followed by1.0 ml of 0.45M (4.5 eq.) HBTU[2-(1H-benzo-triazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosaphate] in DMF. This was followed by the addition of 0.5ml of 2M (10 eq.) DIPEA (diisopropylethylamine) in NMP(N-methylpyrrollidinone). The coupling step was performed for 5 minutesusing 20 watts of microwave power, a max temperature of 75° C., and thesame rate of nitrogen bubbling.

Following the initial coupling step, the reaction vessel was drained towaste and the coupling step repeated. Cycle 2 was then initiated similarto cycle 1. All amino acids were introduced similarly and adouble-coupling strategy was employed throughout the entire sequence.Cycles 1-3, 19-20, 25-26, and 30-39 contained a capping procedureimmediately following the coupling step. Capping was performed by adding7 ml of 0.5M acetic anhydride, containing 0.015M HOBT in NMP, along with2 ml of the 2M DIPEA solution using a multi-step microwave protocol: 50watts of power for 30 seconds (65° C. max temperature), followed by 30seconds of microwave power off, followed by a second round of 30 secondsof microwave power on (50 watts), and then again 30 seconds of nomicrowave power. The resin was then drained and thoroughly washed withDMF. The following amino acids (Advanced Chemtech, Louisville, Ky., USA)were used: Cycle 1: Fmoc-Cys(Trt)-OH; Cycle 2: Fmoc-Ile-OH; Cycle 3:Fmoc-Asn(Trt)-OH; Cycle 4: Fmoc-His(Trt)-OH; Cycle 5: Fmoc-Lys(Boc)-OH;Cycle 6: Fmoc-Trp(Boc)-OH; Cycle 7: Fmoc-Asp(OtBu)-OH; Cycle 8:Fmoc-Asn(Trt)-OH; Cycle 9: Fmoc-Lys(Boc)-OH; Cycle 10: Fmoc-Lys(Boc)-OH;Cycle 11: Fmoc-Gly-OH; Cycle 12: Fmoc-Lys(Boc)-OH; Cycle 13:Fmoc-Gln(Trt)-OH; Cycle 14: Fmoc-Ala-OH; Cycle 15: Fmoc-Leu-OH; Cycle16: Fmoc-Leu-OH; Cycle 17: Fmoc-Trp(Boc)-OH; Cycle 18: Fmoc-Asn(Trt)-OH;Cycle 19: Fmoc-Val-OH; Cycle 20: Fmoc-Phe-OH; Cycle 21:Fmoc-Asp(OtBu)-OH; Cycle 22: Fmoc-Gln(Trt)-OH; Cycle 23:Fmoc-Gln(Trt)-OH; Cycle 24: Fmoc-His(Trt)-OH; Cycle 25: Fmoc-Ile-OH;Cycle 26: Fmoc-Lys(Boc)-OH; Cycle 27: Fmoc-Asp(OtBu)-OH; Cycle 28:Fmoc-Met-OH; Cycle 29: Fmoc-Ala-OH; Cycle 30: Fmoc-Ile-OH; Cycle 31:Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; Cycle 32: Fmoc-Asp(OtBu)-OH; Cycle33: Fmoc-Ser(tBu)-OH; Cycle 34: Fmoc-A6c-OH; Cycle 35: Fmoc-Phe-OH;Cycle 36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; Cycle 37: Fmoc-Glu(OtBu)-OH;Cycle 38: Fmoc-Ala-OH; and Cycle 39: Fmoc-Tyr(tBu)-OH. The couplingprotocol for Fmoc-His(Trt)-OH was a slightly modified version of thestandard protocol. The microwave power was off for the first 2 minutes,followed by 4 minutes with microwave power on (20 watts; max temperatureof 50° C.). Once the peptide backbone was complete, standard piperidinetreatment was used to remove the N-terminal Fmoc group. The resin wasthen thoroughly washed with DMF and then transferred back to the 50 mlconical tube using DMF as the transfer solvent.

The resin was deprotected and cleaved from the resin via treatment with5 ml of the following reagent: 5% TIS, 2% water, 5% (w/v)dithiothrieitol (DTT), 88% TFA, and allowed to mix for 3.5 hours. Thefiltrate was collected into 45 ml of cold anhydrous ethyl ether. Theprecipitate was pelleted for 10 minutes at 3500 RPM in a refrigeratedcentrifuge. The ether was decanted, and the peptide re-suspended infresh ether. The ether workup was performed a total of 2 times.Following the last ether wash, the peptide was allowed to air dry toremove residual ether. The peptide pellet was resuspended in 8 ml ofacetonitrile (Acn) followed by 8 ml of de-ionized water, and allowed tofully dissolve. The peptide solution was then analyzed by massspectrometry. Mass analysis employing electrospray ionization identifieda main product containing a mass of 5011.7 Daltons; corresponding to thedesired linear product. The crude product (approximately 500 mg) wasanalysed by HPLC, employing a 250×4.6 mm C18 column (Phenomenex;Torrance, Calif., USA) using a gradient of 2-80% acetonitrile (0.1% TFA)over 30 minutes. Analytical HPLC identified a product with 34% purity.The crude peptide was then purified on a preparative HPLC equipped witha C18 reverse phase column using a 10-60% acetonirile (0.1% TFA) over 50minutes at a 10 ml/min flowrate. The purified peptide was thenlyophilized yielding 15 mg of peptide. The linear peptide was thenderivatized with N-propylmaleimide (Pma) to generate thepropylsuccinimide (Psu) derivative on the Cysteine side chain. Thepurified linear peptide was brought up in water, adjusted to pH 6.5 withammonium carbonate, at 5 mg/ml. Five equivalents of Pma was added withconstant stirring for 30 seconds. The derivatized peptide solution wasthen analyzed by mass spectrometry. Mass analysis employing electrosprayionization identified a main product containing a mass of 5150.7Daltons; corresponding to the desired Psu derivatized product. Theproduct was then re-purified via preparative HPLC using a similargradient as before. The purified product was analyzed by HPLC for purity(95.10%) and mass spectrometry (5150.9 Daltons) and subsequentlylyophilized.

Example 103 [Orn¹(N—C(O)—(CH₂)₁₂—CH₃), A6c⁷]hGIP(1-42)-OH

Solid-phase peptide synthesis was used to assemble the peptide usingmicrowave-assisted Fmoc Chemistry on a Liberty Peptide Synthesizer (CEM;Matthews, N.C., USA) at the 0.1 mmole scale. Pre-loadedFmoc-Gln(Trt)-Wang resin (0.59 mmole/g; Novabiochem, San Diego, Calif.,USA) was used to generate the C-terminal acid peptide. The resin (0.17g) was placed in a 50 ml conical tube along with 15 ml ofdimethylformamide (DMF) and loaded onto a resin position on thesynthesizer. The resin was then quantitatively transferred to thereaction vessel via the automated process. The standard Libertysynthesis protocol for 0.1 mmole scale synthesis was used. This protocolinvolves deprotecting the N-terminal Fmoc moiety via an initialtreatment with 7 ml of 20% piperidine, containing 0.1MN-hydroxybenzotriazole (HOBT), in DMF. The initial deprotection step wasfor 30 seconds with microwave power (45 watts, maximum temperature of75° C.), and nitrogen bubbling (3 seconds on/7 seconds off). Thereaction vessel was then drained and a second piperidine treatment,identical to the first treatment, except that it was for a 3-minuteduration. The resin was then drained and thoroughly washed with DMFseveral times. The protected amino acid, Fmoc-Thr(tBu)-OH, prepared as0.2M stock solution in DMF, was then added (2.5 ml, 5 eq.), followed by1.0 ml of 0.45M (4.5 eq.) HBTU[2-(1H-benzo-triazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosaphate] in DMF. This was followed by the addition of 0.5ml of 2M (10 eq.) DIPEA (diisopropylethylamine) in NMP(N-methylpyrrollidinone). The coupling step was performed for 5 minutesusing 20 watts of microwave power, a max temperature of 75° C., and thesame rate of nitrogen bubbling.

Following the initial coupling step the reaction vessel was drained towaste and the coupling step repeated. Cycle 2 was then initiated similarto cycle 1. All amino acids were introduced similarly and adouble-coupling strategy was employed throughout the entire sequence.Cycles 1-3, 19-20, 25-26, and 30-39 contained a capping procedureimmediately following the coupling step. Capping was performed by adding7 ml of 0.5M acetic anhydride, containing 0.015M HOBT in NMP, along with2 ml of the 2M DIPEA solution using a multi-step microwave protocol: 50watts of power for 30 seconds (65° C. max temperature), followed by 30seconds of microwave power off, followed by a second round of 30 secondsof microwave power on (50 watts), and then again 30 seconds of nomicrowave power. The resin was then drained and thoroughly washed withDMF. The following amino acids (Advanced Chemtech, Louisville, Ky., USA)were used: Cycle 1: Fmoc-Thr(tBu)-OH; Cycle 2: Fmoc-Ile-OH; Cycle 3:Fmoc-Asn(Trt)-OH; Cycle 4: Fmoc-His(Trt)-OH; Cycle 5: Fmoc-Lys(Boc)-OH;Cycle 6: Fmoc-Trp(Boc)-OH; Cycle 7: Fmoc-Orn(Mtt)-OH; Cycle 8:Fmoc-Asn(Trt)-OH; Cycle 9: Fmoc-Lys(Boc)-OH; Cycle 10: Fmoc-Lys(Boc)-OH;Cycle 11: Fmoc-Gly-OH; Cycle 12: Fmoc-Lys(Boc)-OH; Cycle 13:Fmoc-Gln(Trt)-OH; Cycle 14: Fmoc-Ala-OH; Cycle 15: Fmoc-Leu-OH; Cycle16: Fmoc-Leu-OH; Cycle 17: Fmoc-Trp(Boc)-OH; Cycle 18: Fmoc-Asn(Trt)-OH;Cycle 19: Fmoc-Val-OH; Cycle 20: Fmoc-Phe-OH; Cycle 21:Fmoc-Asp(OtBu)-OH; Cycle 22: Fmoc-Gln(Trt)-OH; Cycle 23:Fmoc-Gln(Trt)-OH; Cycle 24: Fmoc-His(Trt)-OH; Cycle 25: Fmoc-Ile-OH;Cycle 26: Fmoc-Lys(Boc)-OH; Cycle 27: Fmoc-Asp(OtBu)-OH; Cycle 28:Fmoc-Met-OH; Cycle 29: Fmoc-Ala-OH; Cycle 30: Fmoc-Ile-OH; Cycle 31:Fmoc-Tyr(tBu)-Ser(psiMe,Me,Pro)-OH; Cycle 32: Fmoc-Asp(OtBu)-OH; Cycle33: Fmoc-Ser(tBu)-OH; Cycle 34: Fmoc-A6c-OH; Cycle 35: Fmoc-Phe-OH;Cycle 36: Fmoc-Gly-Thr(psiMe,Me,Pro)-OH; Cycle 37: Fmoc-Glu(OtBu)-OH;Cycle 38: Fmoc-Ala-OH; and Cycle 39: Boc-Tyr(tBu)-OH. The couplingprotocol for Fmoc-His(Trt)-OH was a slightly modified version of thestandard protocol. The microwave power was off for the first 2 minutes,followed by 4 minutes with microwave power on (20 watts; max temperatureof 50° C.). Once the peptide backbone was complete, the resin wastreated with 12 ml of 1% trifluoroacetic acid (TFA)/5%triisopropylsilane (TIS) in dichloromethane (DCM) for 5 minutes and a N₂sparge rate of 5 seconds on and 10 seconds off. The resin was thendrained and again treated with the 1% TFA/5% TIS in DCM solution for 5minutes. This was performed a total of 7 times to effectively remove theMtt moiety from the Ornithine side chain. The resin was thoroughlywashed with DCM several times, and then treated with the standardpiperidine treatment in order to neutralize residual TFA salt on the δNof ornithine. Myristic acid, (CH₃—(CH₂)₁₂—COOH; Aldrich, St. Louis, Mo.,USA) prepared as a 0.2M solution in DMF, was coupled to the ornithineside chain using the standard amino acid coupling protocol. The resinwas then thoroughly washed with DMF and then transferred back to the 50ml conical tube using DMF as the transfer solvent.

The resin was deprotected and cleaved from the resin via treatment with5 ml of the following reagent: 5% TIS, 2% water, 5% (w/v)dithiothrieitol (DTT), 88% TFA, and allowed to mix for 3.5 hours. Thefiltrate was collected into 45 ml of cold anhydrous ethyl ether. Theprecipitate was pelleted for 10 minutes at 3500 RPM in a refrigeratedcentrifuge. The ether was decanted, and the peptide re-suspended infresh ether. The ether workup was performed a total of 2 times.Following the last ether wash the peptide was allowed to air dry toremove residual ether. The peptide pellet was resuspended in 8 ml ofacetonitrile (Acn) followed by 8 ml of de-ionized water, and allowed tofully dissolve. The peptide solution was then analyzed by massspectrometry. Mass analysis employing electrospray ionization identifieda main product containing a mass of 5205.1 Daltons; corresponding to thedesired linear product. The crude product (approximately 500 mg) wasanalysed by HPLC, employing a 250×4.6 mm C18 column (Phenomenex;Torrance, Calif., USA) using a gradient of 2-80% acetonitrile (0.1% TFA)over 30 minutes. Analytical HPLC identified a product with 50% purity.The peptide was then purified on a preparative HPLC equipped with a C18column using a similar elution gradient. The purified product wasre-analyzed by HPLC for purity (95.50%) and mass spectrometry (5156.7Daltons) and subsequently lyophilized Following lyophillization, 6.2 mgof purified product was obtained representing a 1.2% yield.

Other peptides of the invention can be prepared by a person of ordinaryskill in the art using synthetic procedures analogous to those disclosedin the foregoing examples. Physical data for the compounds exemplifiedherein are given in Table 1.

TABLE 1 Example Mol. Wt. Mol. Wt. % Purity Number (Expected) (ESI-MS)(HPLC) 1 4995.63 4996.5 95.67 2 4967.62 4968.2 97.88 3 4969.55 4971.399.90 4 4981.60 4982.9 99.90 5 5007.64 5007.5 96.32 6 4995.59 4994.896.17 7 4995.59 4996.6 95.84 8 4969.55 4968.9 93.98 9 4995.63 4996.893.30 10 5025.66 5027.0 9792 11 3556.04 3557.3 96.82 12 3543.99 3544.698.93 13 3543.99 3545.1 97.36 14 3574.06 3575.4 93.62 15 3530.00 3531.195.36 16 3517.95 3525.8 99.00 17 3544.03 3545.0 99.90 18 3516.02 3516.396.03 19 3544.03 3544.1 99.90 20 3517.95 3518.1 99.90 21 5005.60 5005.699.90 22 5037.67 5037.9 94.20 23 4993.62 4993.3 98.10 24 5019.63 5019.499.00 25 4975.58 4975.7 99.30 26 5003.59 5003.6 99.00 27 5003.59 5003.892.90 28 5003.59 5004.0 95.20 29 5015.64 5016.2 97.40 30 5005.60 5005.499.00 31 3539.98 3540.0 98.60 32 3525.95 3526.2 95.30 33 3525.99 3525.899.90 34 3551.99 3552.3 99.90 35 3523.93 3524.0 97.,70 36 3580.04 3580.099.90 37 5003.59 5003.5 99.90 38 3538.00 3538.3 99.99 39 3551.99 3552.197.40 40 5005.60 5005.5 99.00 41 4989.60 4989.6 99.00 42 4991.57 4991.999.00 43 5009.61 5009.5 99.00 44 4989.56 4989.5 99.80 45 4977.59 4977.499.00 46 3570.07 3569.8 99.00 47 3560.03 3557.8 99.00 48 5161.42 5161.399.90 49 5017.66 5018.0 99.90 50 5038.7 5038.6 99.90 51 5082.53 5082.599.90 52 3558.01 2559.8 99.00 53 5021.67 5021.5 94.70 54 5003.63 5004.099.00 55 4991.57 4991.3 99.00 56 5015.60 5015.6 98.70 57 4993.59 4993.896.50 58 4977.55 4977.8 99.00 59 4975.53 4975.0 99.00 60 5011.63 5011.599.00 61 5015.64 5015.9 99.00 62 4947.57 4948.1 99.90 63 4961.59 4961.199.90 64 4961.59 4960.6 99.90 65 4979.63 4980.0 99.00 66 5027.68 5027.399.90 67 4981.60 4981.3 99.70 68 4963.56 4963.9 99.90 69 5009.64 5009.899.90 70 4963.56 4963.3 99.90 71 5007.62 5007.2 98.60 72 4959.57 4959.999.90 73 5150.81 5150.9 95.10 74 4989.67 4989.8 98.80 75 4965.60 4966.099.99 76 4929.51 4929.6 99.00 77 4975.64 4975.6 97.12 78 5138.75 5139.095.60 79 5137.81 5138.1 99.90 80 5114.77 5114.3 99.90 81 5065.70 5065.698.90 82 5037.71 5037.9 99.90 83 4983.64 4983.8 99.90 84 4961.55 4961.599.90 85 5136.82 5136.6 99.90 86 5137.81 5137.6 99.90 87 4991.64 4991.798.80 88 4985.61 4985.2 99.90 89 5031.69 5031.8 99.90 90 5194.86 5194.399.90 91 4945.55 4945.0 99.90 92 3506.01 3505.9 99.90 93 5137.74 5137.599.90 94 5123.74 5124.0 98.30 95 5251.91 5252.0 98.60 96 3518.02 3518.299.90 97 3511.99 3512.0 98.80 98 3524.04 3523.8 99.90 99 5123.74 5123.599.90 100 5123.74 5123.5 97.90 101 4982.59 4982.0 99.90 102 4969.624969.4 99.90 103 5156.92 5156.7 95.50 104 5005.63 5005.8 97.19 1055144.78 5144.8 95.62 106 5017.68 5018.4 96.00 107 5039.71 5040.4 99.90108 3509.99 3509.8 99.90 109 3526.02 3525.7 99.00 110 3538.07 3538.199.99 111 3520.03 3519.9 99.99 112 3532.4 3532.0 99.90 113 5017.665018.0 99.90 117 5130.8 5130.8 >99 118 5112.7 5112.9 >99 119 5126.75126.5 >99 121 3536.0 3536.4 97.0 122 3693.2 3693.5 98.2 123 5138.85138.5 99.9

Functional Assays

A. In Vitro hGIP Receptor Binding Assay

Membranes for in vitro receptor binding assays were prepared byhomogenizing the CHO-K1 clonal cells expressing the human recombinantGIP receptor, with a Brinkman Polytron (setting 6, 15 sec), in ice-cold50 mM Tris-HCl and then subjected to two centrifugations at 39,000 g for10 minutes, with a resuspension in fresh buffer in between. For theassay, aliquots of the washed membrane preparations were incubated (100minutes at 25° C. with 0.05 nM [¹²⁵I]GIP (approximately 2200 Ci/mmol) in50 mM Tris-HCl, 0.1 mg/ml bacitracin, and 0.1% BSA. The final assayvolume was 0.5 ml. The incubations were terminated by rapid filtrationthrough GF/C filters (pre-soaked in 0.5% polyethylenimine) using aBrandel filtration manifold. Each tube and filter were then washed threetimes with 5-ml aliquots of ice-cold buffer. Specific binding wasdefined as the total radioligand bound minus that bound in the presenceof 1000 nM GIP. In vitro hGIP receptor binding data for the compoundsexemplified herein are given in Table 2.

B. Human and Rat Plasma Half-Life Assay

GIP peptide (50 μL 1 mg/ml) was added to 450 μL plasma (human or rat),vertexed briefly and incubated at 37° C. 50 μL was removed at varioustimes, like at 0, 1, 2, 3, 4, 8, 24, 32, 48, 56, 72 hours, mixed with 5μL formic acid and 150 μL acetonitrile in a microcentrifuge tube,vertexed, and centrifuged for 10 minutes at 10K rpm. The supernatant wastransferred to an injection vial and analyzed by LC-MS. The LC-MS systemconsisted of an API4000 mass spectrometer with an ESI probe. Positiveion mode and full scan detection were used. HPLC separation was carriedout on a Luna 3μ C8 (2), 2×30 mm column with a gradient from 90% A to90% B in 10 minutes at a flow rate of 0.3 ml/min. Buffer A was 1% formicacid in water and buffer B was 1% formic acid acetonitrile. Human andrat plasma half-life data for the compounds exemplified herein are givenin Table 2.

TABLE 2 Example Human Plasma Rat Plasma Number Ki (nM) T½ (hr) T½ (hr) 11.20 >48 3.9 2 2.66 9.4 5.6 3 0.75 >48 5.5 4 4.08 >48 4.8 5 2.26 >48 6.16 0.41 >48 8.6 7 1.65 37.1 5.3 8 4.98 >48 4.5 9 16.25 >48 9.2 1080.07 >48 4.0 11 2.05 44.4 >48 12 0.27 20.5 >48 13 0.98 35.4 >48 14106.63 34.8 48 15 3.33 28.6 46.5 16 0.53 43.9 >48 17 15.93 17.4 55.0 185.38 11.3 44.4 19 0.37 27.2 >48 20 1.84 25.4 42 21 0.30 >48 12.3 226.96 >48 14.2 23 0.87 >48 6.7 24 2.06 >48 24.8 25 1.33 >48 8.4 26 2.54N/A N/A 27 120.95 >48 9.3 28 1.09 >48 11.6 29 1.17 >48 7.3 30 1.22 >4813.4 31 1.04 36.5 31.4 32 4.90 >48 28.3 33 1.39 >48 34 34 25.80 >48 2335 2.32 >48 39.4 36 46.97 23.7 29.2 37 1.06 >48 14.0 38 0.73 49.1 >54 391.19 42.3 43.3 40 15.89 7.7 4.9 41 0.73 15.9 13.3 42 0.07 10.6 6.2 430.30 8.8 7.7 44 0.63 9.5 7.5 45 0.29 18.2 11.6 46 0.09 12.2 >54 47 0.3345.3 30.8 48 0.15 >56 >54 49 0.09 >56 45.0 50 0.16 48.1 >54 51 0.83 33.812.7 52 0.03 14.0 28.2 53 0.08 33.3 51.7 54 0.43 >56 44.1 55 0.45 8.811.7 56 34.38 16.0 9.2 57 0.05 30.5 13.8 58 0.69 37.6 16.7 59 0.22 24.013.1 60 0.05 26.0 10.5 61 0.18 >48 45.3 62 666.95 11.4 1.4 63 330.1114.2 1.4 64 727.37 41.3 47.5 65 N/A 14.3 1.5 66 N/A 19.1 8.8 67 N/A >331.6 68 N/A >48 1.9 69 N/A 36.9 1.8 70 N/A >33 1.5 71 N/A >31 4.8 72 N/A10.7 0.45 73 63.57 N/A N/A 74 N/A 16.3 1.3 75 N/A 26.1 1.9 76 N/A 55.91.0 77 N/A 43.3 1.5 78 15.97 10.1 11.2 79 13.78 N/A 14.3 80 5.05 >54 5.581 635.48 8.2 6.1 82 503.00 9.7 10.2 83 N/A 32.4 1.1 84 909.50 3.3 1.985 288.33 7.3 3.5 86 355.54 4.2 7.0 87 N/A 38.7 3.4 88 N/A >48 4.4 89753.50 >48 11.8 90 75.78 11.3 4.8 91 214.00 13.4 1.0 92 86.79 12.0 1.693 0.94 N/A N/A 94 2.59 N/A N/A 95 N/A N/A N/A 96 870.94 N/A N/A 97181.00 N/A N/A 98 65.85 N/A N/A 99 1.51 N/A N/A 100 22.68 N/A N/A 1012.25 47.5 13.4 102 647.50 54.1 1.7 103 21.47 6.8 >72 104 0.59 20.2 14.8105 0.56 19.1 6.9 106 0.36 >55 9.2 107 6.67 N/A N/A 108 0.07 46.2 45.6109 333.46 27.2 47.8 110 216.24 13.7 25.8 111 N/A >54 >54 112 34.1259.7 >72 113 0.19 61.9 27.0 117 0.97 25.2 10.5 118 0.87 >42 11.2 1190.66 35.7 15.4 121 0.46 N/A N/A 122 0.87 N/A N/A 123 0.55 N/A N/A

In comparison to the data listed in Table 2, the in vitro hGIP receptorbinding data, and human and rat plasma half-life data for[Pro³]hGIP(1-42)-OH, a compound disclosed in PCT publication WO00/58360, were measured under the same experimental conditions asdescribed hereinabove to be 170.8 nM, and 10.8 hours and 0.8 hours,respectively.

C. Determination of Cyclic AMP Stimulation

1×105 CHO-K1 cells expressing the human recombinant GIP receptor orRIN-5F insulinoma cells were seeded overnight into 24-well cell cultureplates (Corning Incorporate, Corning, N.Y., USA). For the assay, thecells were preincubated in 500 μl of Hanks balanced salt solution(Sigma, St. Louis, Mo., USA) with 0.55 mM IBMX (Sigma, St. Louis, Mo.,USA) adjusted to pH 7.3 for 10 minutes. GIP or its analogs was thenadded at a concentration of 100 nM. Following a 30-minute incubation at37° C., the plates were placed on ice and 500 μl of ice-cold absoluteethanol was added to stop the reaction. The contents of the wells werecollected, spun at 2,700 g for 20 minutes at 4° C. to remove cellulardebris. The cAMP levels in the supernatants were determined byradioimmunoassay (New England Nuclear, Boston, Mass., USA).

D. Determination of In Vivo Insulin Secretion in Normal Rats

Male Sprague Dawley rats with a body weight of approximately 275-300 gwere used as experimental subjects. The day prior to the treatment,right atrial cannulae were implanted via the jugular vein underchlorohydrate. Each cannula was filled with 100 u/ml heparin saline andtied. The rats were fasted for approximately 18 hours prior to dosingwith the compound or the vehicle (saline/0.25% BSA). The day of theexperiment, aliquots of compound were thawed, brought to roomtemperature and vortexed thoroughly. A careful check was made for anysign of compound coming out of solution. 10 minutes prior tocompound/glucose injection, a 500 μl blood sample was withdrawn andreplaced with an equal volume of heparinized saline (10 u/ml). At time0, a 500 μl blood sample was withdrawn through the cannula. Next, eitherthe vehicle or the appropriate dose of the compound was injected intothe cannula and pushed in with the glucose (1 g/kg) or vehicle solution.Finally, 500 μl of volume of heparinized saline (10 u/ml) was used topush in the remaining glucose through the cannula. Additional 500 μlblood samples were withdrawn at 2.5, 5, 10, and 20-minute post-glucosedosing; each immediately followed by a bolus, iv injection of 500 μlheparinized saline (10 u/ml) through the cannula. The plasma wascollected from the blood samples by centrifugation, and stored at −20°C. until assay for insulin content. Numerical values of the totalinsulin secretion, which show the in vivo effects of the compounds ofExamples 105, 106, 118, and 119, are summarized in Table 3.

TABLE 3 AUC Vehicle/Vehicle 20.54 Vehicle/Glucose 4.11 Example 105114.70 Example 106 161.73 Example 118 88.22 Example 119 167.48

Administration

The peptides of this invention can be provided in the form ofpharmaceutically acceptable salts. Examples of such salts include, butare not limited to, those formed with organic acids (e.g., acetic,lactic, maleic, citric, malic, ascorbic, succinic, benzoic,methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids(e.g., hydrochloric acid, sulfuric acid, or phosphoric acid), andpolymeric acids (e.g., tannic acid, carboxymethyl cellulose, polylactic,polyglycolic, or copolymers of polylactic-glycolic acids). A typicalmethod of making a salt of a peptide of the present invention is wellknown in the art and can be accomplished by standard methods of saltexchange. Accordingly, the TFA salt of a peptide of the presentinvention (the TFA salt results from the purification of the peptide byusing preparative HPLC, eluting with TFA containing buffer solutions)can be converted into another salt, such as an acetate salt bydissolving the peptide in a small amount of 0.25 N acetic acid aqueoussolution. The resulting solution is applied to a semi-prep HPLC column(Zorbax, 300 SB, C-8). The column is eluted with (1) 0.1N ammoniumacetate aqueous solution for 0.5 hrs, (2) 0.25N acetic acid aqueoussolution for 0.5 hrs, and (3) a linear gradient (20% to 100% of solutionB over 30 minutes) at a flow rate of 4 ml/min (solution A is 0.25Nacetic acid aqueous solution; solution B is 0.25N acetic acid inacetonitrile/water, 80:20). The fractions containing the peptide arecollected and lyophilized to dryness.

The dosage of active ingredient in the compositions of this inventionmay be varied; however, it is necessary that the amount of the activeingredient be such that a suitable dosage form is obtained. The selecteddosage depends upon the desired therapeutic effect, on the route ofadministration, and on the duration of the treatment. In general, aneffective dosage for the activities of this invention is in the range of1×10⁻⁷ to 200 mg/kg/day, preferably 1×10⁻⁴ to 100 mg/kg/day, which canbe administered as a single dose or divided into multiple doses.

The compounds of this invention can be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous or subcutaneousinjection, or implant), nasal, vaginal, rectal, sublingual, or topicalroutes of administration, and can be formulated with pharmaceuticallyacceptable carriers to provide dosage forms appropriate for each routeof administration.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound is admixed with at least one inert pharmaceutically acceptablecarrier such as sucrose, lactose, or starch. Such dosage forms can alsocomprise, as is normal practice, additional substances other than suchinert diluents, e.g., lubricating agents such as magnesium stearate. Inthe case of capsules, tablets and pills, the dosage forms may alsocomprise buffering agents. Tablets and pills can additionally beprepared with enteric coatings.

Liquid dosage forms for oral administration include, without limitation,pharmaceutically acceptable emulsions, solutions, suspensions, syrups,elixirs, and the like, containing inert diluents commonly used in theart, such as water. Besides such inert diluents, compositions can alsoinclude adjuvants, such as wetting agents, emulsifying and suspendingagents, and sweetening, flavoring and perfuming agents.

Preparations according to this invention for parenteral administrationinclude, without limitation, sterile aqueous or non-aqueous solutions,suspensions, emulsions, and the like. Examples of non-aqueous solventsor vehicles include propylene glycol, polyethylene glycol, vegetableoils, such as olive oil and corn oil, gelatin, and injectable organicesters such as ethyl oleate. Such dosage forms may also containadjuvants such as preserving, wetting, emulsifying, and dispersingagents. They may be sterilized by, for example, filtration through abacteria-retaining filter, by incorporating sterilizing agents into thecompositions, by irradiating the compositions, or by heating thecompositions. They can also be manufactured in the form of sterile solidcompositions which can be dissolved in sterile water, or some othersterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferablysuppositories which may contain, in addition to the active substance,excipients such as coca butter or a suppository wax.

Compositions for nasal or sublingual administration are also preparedwith standard excipients well known in the art.

Further, a compound of this invention can be administered in a sustainedrelease composition such as those described in the following patents andpatent applications. U.S. Pat. No. 5,672,659 teaches sustained releasecompositions comprising a bioactive agent and a polyester. U.S. Pat. No.5,595,760 teaches sustained release compositions comprising a bioactiveagent in a gelable form. U.S. Pat. No. 5,821,221 teaches polymericsustained release compositions comprising a bioactive agent andchitosan. U.S. Pat. No. 5,916,883 teaches sustained release compositionscomprising a bioactive agent and cyclodextrin. PCT publicationWO99/38536 teaches absorbable sustained release compositions of abioactive agent. PCT publication WO00/04916 teaches a process for makingmicroparticles comprising a therapeutic agent such as a peptide in anoil-in-water process. PCT publication WO00/09166 teaches complexescomprising a therapeutic agent such as a peptide and a phosphorylatedpolymer. PCT publication WO00/25826 teaches complexes comprising atherapeutic agent such as a peptide and a polymer bearing anon-polymerizable lactone.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents and other references mentioned herein are herebyincorporated by reference, each in its entirety.

What is claimed is:
 1. A compound of formula (I),(R²R³)-A¹-A²-A³-A⁴-A⁵-A⁶-A⁷-A⁸-A⁹-A¹⁰-A¹¹-A¹²-A¹³-A¹⁴-A¹⁵-A¹⁶-A¹⁷-A¹⁸-A¹⁹-A²⁰-A²¹-A²²-A²³-A²⁴-A²⁵-A²⁶-A²⁷-A²⁸-A²⁹-A³⁰-A³¹-A³²-A³³-A³⁴-A³⁵-A³⁶-A³⁷-A³⁸-A³⁹-A⁴⁰-A⁴¹-A⁴²-A⁴³-R¹wherein: A¹ is Tyr; A² is Aib; A³ is Glu; A⁴ is Gly, Acc, Aib, or β-Ala;A⁵ is Thr, Acc, Aib, or Ser; A⁶ is Phe, Acc, Aib, Aic, Cha, 1Nal, 2Nal,2-Pal, 3-Pal, 4-Pal, (X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Trp; A⁷ is Ile, Abu, Acc,Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; A⁸ is Ser, Aib, or Thr; A⁹ isAsp, Aib, or Glu; A¹⁰ is Tyr, Acc, Cha, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal,Phe, or (X⁴,X⁵,X⁶,X⁷,X⁸)Phe; A¹¹ is Ser, Acc, Aib, Nle, or Thr; A¹² isIle, Abu, Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; A¹³ is Ala,Acc, Aib, β-Ala, D-Ala, Gly, or Ser; A¹⁴ is Met, Abu, Acc, Aib, Ala,Cha, Ile, Leu, Nle, Phe, Tle, or Val; A¹⁵ is Asp, Aib, or Glu; A¹⁶ isLys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), orPen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃); A¹⁷ is Ile, Abu,Acc, Aib, Ala, Cha, Leu, Nle, Phe, Tle, or Val; A¹⁸ is His, Amp, Arg,2-Pal, 3-Pal, 4-Pal, Phe, or Tyr; A¹⁹ is Gln, Aib, or Asn; A²⁰ is Gln,Aib, or Asn; A²¹ is Asp, Aib, or Glu; A²² is Phe, Acc, Aib, Aic, Cha,1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, (X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Trp; A²³ isVal, Abu, Acc, Aib, Ala, Cha, Ile, Leu, Nle, or Tle; A²⁴ is Asn, Aib, orGln; A²⁵ is Trp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe, or(X⁴,X⁵,X⁶,X⁷,X⁸)Phe; A²⁶ is Leu, Acc, Aib, Cha, Ile, Nle, Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Tle; A²⁷ is Leu, Acc, Aib, Cha, Ile, Nle, Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe, or Tle; A²⁸ is Ala, Acc, or Aib; A²⁹ is Gln, Aib,Asn, or deleted; A³⁰ is Lys, Amp, Apc, Arg, hArg, Orn,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), Cys(succinimide-N-alkyl),hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³¹ isGly, Acc, Aib, β-Ala, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), His,Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³² isLys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³³ isLys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³⁴ isAsn, Aib, Gln, Ser, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³⁵ isAsp, Aib, Glu, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), Cys(succinimide-N-alkyl),hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³⁶ isTrp, Acc, Aib, 1Nal, 2Nal, 2-Pal, 3-Pal, 4-Pal, Phe,(X⁴,X⁵,X⁶,X⁷,X⁸)Phe, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³⁷ isLys, Amp, Apc, Arg, hArg, Orn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³⁸ isHis, Amp, 2-Pal, 3-Pal, 4-Pal, Phe, Tyr, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A³⁹ isAsn, Aib, Gln, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), Cys(succinimide-N-alkyl),hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A⁴⁰ isIle, Acc, Aib, Ser, Thr, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A⁴¹ isThr, Acc, Aib, Asn, Gln, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A⁴² isGln, Acc, Aib, Asn, HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O),Cys(succinimide-N-alkyl), hCys(succinimide-N-alkyl),Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(t)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; A⁴³ isAcc, Aib, Ala, Asp, Gln, His, Phe, Thr, Trp,HN—CH((CH₂)_(n)—N(R⁴R⁵))—C(O), Cys(succinimide-N-alkyl),hCys(succinimide-N-alkyl), Pen(succinimide-N-alkyl),Cys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),hCys(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Pen(succinimide-N—(CH₂)_(x)—C(O)—NH—(CH₂)_(y)—CH₃),Cys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),hCys(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃),Pen(succinimide-N—(CH₂)_(s)—NH—C(O)—(CH₂)_(t)—CH₃), or deleted; R¹ isOH, NH₂, (C₁-C₃₀)alkoxy, or NH—X²—CH₂—Z⁰, wherein X² is a (C₀-C₃₀)hydrocarbon moiety and Z⁰ is H, OH, CO₂H, or CONH₂; each of R², R³, R⁴and R⁵ is independently selected from the group consisting of H,(C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₁-C₃₀)acyl, (C₂-C₃₀)alkenyl,(C₂-C₃₀)alkynyl, aryl(C₁-C₃₀)alkyl, aryl(C₁-C₃₀)acyl, substituted(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)heteroalkyl, substituted(C₁-C₃₀)acyl, substituted (C₂-C₃₀)alkenyl, substituted (C₂-C₃₀)alkynyl,substituted aryl(C₁-C₃₀)alkyl, and substituted aryl(C₁-C₃₀)acyl;provided that when R² is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted(C₁-C₃₀)acyl, or substituted aryl(C₁-C₃₀)acyl, then R³ is H,(C₁-C₃₀)alkyl, (C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted(C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl; further provided thatwhen R⁴ is (C₁-C₃₀)acyl, aryl(C₁-C₃₀)acyl, substituted (C₁-C₃₀)acyl, orsubstituted aryl(C₁-C₃₀)acyl, then R⁵ is H, (C₁-C₃₀)alkyl,(C₁-C₃₀)heteroalkyl, (C₂-C₃₀)alkenyl, (C₂-C₃₀)alkynyl,aryl(C₁-C₃₀)alkyl, substituted (C₁-C₃₀)alkyl, substituted(C₁-C₃₀)heteroalkyl, substituted (C₂-C₃₀)alkenyl, substituted(C₂-C₃₀)alkynyl, or substituted aryl(C₁-C₃₀)alkyl; n is, independentlyfor each occurrence, an integer from 1 to 5 inclusive; s, t, x and yeach is, independently for each occurrence, an integer from 1 to 30inclusive; X⁴, X⁵, X⁶, X⁷ and X⁸ each is, independently for eachoccurrence, H, F, Cl, Br, I, (C₁₋₁₀)alkyl, substituted (C₁₋₁₀)alkyl,aryl, substituted aryl, OH, NH₂, NO₂, or CN; provided that at least oneamino acid residue at positions 4-43 is not the amino acid residue ofthe corresponding position in native hGIP; and optionally furthercomprising a covalently linked PEG moiety; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein: A⁴is Gly or Aib; A⁵ is Thr, A5c, or Aib; A⁶ is Phe or A6c; A⁷ is Ile, A5c,A6c, or Aib; A⁸ is Ser or Aib; A⁹ is Asp or Aib; A¹⁰ is Tyr; A¹¹ is Ser,A5c, A6c, Aib, or Nle; A¹² is Ile, A5c, or Aib; A¹³ is Ala or Aib; A¹⁴is Met, A5c, A6c, or Nle; A¹⁵ is Asp; A¹⁶ is Lys; A¹⁷ is Ile or A6c; A¹⁸is His; A¹⁹ is Gln; A²⁰ is Gln; A²¹ is Asp; A²² is Phe; A²³ is Val; A²⁴is Asn; A²⁵ is Trp; A²⁶ is Leu or A6c; A²⁷ is Leu or A6c; A²⁸ is Ala orAib; A²⁹ is Gln; A³⁰ is Lys; A³¹ is Gly, Aib, Cys(Psu), His, or deleted;A³² is Lys, Cys(Psu), or deleted; A³³ is Lys, Cys(Psu), or deleted; A³⁴is Asn, Cys(Psu), or deleted; A³⁵ is Asp, Cys(Psu), or deleted; A³⁶ isTrp, Cys(Psu), or deleted; A³⁷ is Lys, Cys(Psu), or deleted; A³⁸ is His,Cys(Psu), or deleted; A³⁹ is Asn, Cys(Psu), or deleted; A⁴⁰ is Ile, A5c,A6c, Cys(Psu), or deleted; A⁴¹ is Thr, A5c, A6c, Aib, Cys(Psu), ordeleted; A⁴² is Gln or deleted; A⁴³ is Cys(Psu), Gln, His, or deleted;or a pharmaceutically acceptable salt thereof.
 3. A compound accordingto claim 2, wherein said compound is: (SEQ ID NO: 4)(Aib^(2, 11))hGIP(1-42)-OH; (SEQ ID NO: 5) (Aib^(2, 9))hGIP(1-42)-OH;(SEQ ID NO: 6) (Aib^(2, 7))hGIP(1-42)-OH; (SEQ ID NO: 7)(Aib^(2, 5))hGIP(1-42)-OH; (SEQ ID NO: 8) (Aib², A5c⁵)hGIP(1-42)-OH;(SEQ ID NO: 9) (Aib², A5c⁷)hGIP(1-42)-OH; (SEQ ID NO: 10)(Aib², A5c¹²)hGIP(1-42)-OH; (SEQ ID NO: 11) (Aib^(2, 12))hGIP(1-42)-OH;(SEQ ID NO: 12) (Aib^(2, 8))hGIP(1-42)-OH; (SEQ ID NO: 13)(Aib^(2, 4))hGIP(1-42)-OH; (SEQ ID NO: 14) (Aib², A5c⁵)hGIP(1-30)-NH₂;(SEQ ID NO: 15) (Aib², A5c⁷)hGIP(1-30)-NH₂; (SEQ ID NO: 16)(Aib², A5c¹²)hGIP(1-30)-NH₂; (SEQ ID NO: 17) (Aib^(2, 4))hGIP(1-30)-NH₂;(SEQ ID NO: 18) (Aib^(2, 5))hGIP(1-30)-NH₂; (SEQ ID NO: 19)(Aib^(2, 7))hGIP(1-30)-NH₂; (SEQ ID NO: 20) (Aib^(2, 8))hGIP(1-30)-NH₂;(SEQ ID NO: 21) (Aib^(2, 9))hGIP(1-30)-NH₂; (SEQ ID NO: 22)(Aib^(2, 11))hGIP(1-30)-NH₂; (SEQ ID NO: 23)(Aib^(2, 12))hGIP(1-30)-NH₂; (SEQ ID NO: 24)(Aib^(2, 13), A6c⁷, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 25)(Aib^(2, 31), A6c⁷)hGIP(1-42)-OH; (SEQ ID NO: 26)(Aib^(2, 41), A6c⁷)hGIP(1-42)-OH; (SEQ ID NO: 27)(Aib^(2, 31), A6c⁷, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 28)(Aib^(2, 41), A6c⁷, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 29)(Aib², A6c^(7, 26), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 30)(Aib², A6c^(7, 27), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 31)(Aib², A6c^(7, 40), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 32)(Aib², A6c^(7, 41), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 33)(Aib^(2, 28), A6c⁷, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 34)(Aib², A6c⁷, Nle¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 35)(Aib², A5c⁷, Nle¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 36)(Aib^(2, 11), Nle¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 39)(A6c^(2, 7), Nle¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 40)(Aib², A6c^(7, 17), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 41)(Aib^(2, 11), A6c¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 42)(Aib², A6c^(7,) ¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 44)(Aib^(2, 11), A6c¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 45)(Aib², A6c¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 46) (Aib², A6c⁷)hGIP(1-42)-OH;(SEQ ID NO: 47) (Aib², A5c⁷, A6c¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 48)(Aib^(2, 11), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 49)(Aib², A5c¹¹)hGIP(1-30)-NH₂; (SEQ ID NO: 50)(Aib^(2, 13))hGIP(1-30)-NH₂; (SEQ ID NO: 51)(Aib², A5c¹¹, A6c¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 52)(Aib^(2, 13), Nle¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 53)(Aib², A5c¹¹, Nle¹⁴)hGIP(1-30)-NH₂; (SEQ ID NO: 54)(Aib², A6c^(7,) ¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 55)(Aib², A6c⁷)hGIP(1-30)-NH₂; (SEQ ID NO: 56) (Aib², A5c¹¹)hGIP(1-42)-OH;(SEQ ID NO: 57) (Aib², A5c¹¹, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 58)(Aib², A6c⁷, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 60)(Aib^(2, 13), Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 61)(Aib², A5c⁷, Nle¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 62)(Aib², A5c^(7,) ¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 63)(Aib^(2, 13))hGIP(1-42)-OH; (SEQ ID NO: 64)(Aib², A5c¹¹, A6c¹⁴)hGIP(1-42)-OH; (SEQ ID NO: 76)[Aib², A6c⁷, Cys(Psu)⁴¹]hGIP(1-42)-OH; (SEQ ID NO: 81)[Aib², A6c⁷, Cys(Psu)⁴⁰]hGIP(1-42)-OH; (SEQ ID NO: 82)[Aib², A6c⁷, Cys(Psu)³⁹]hGIP(1-42)-OH; (SEQ ID NO: 83)[Aib², A6c⁷, Cys(Psu)³⁸]hGIP(1-42)-OH; (SEQ ID NO: 84)[Aib², A6c⁷, Cys(Psu)³⁶]hGIP(1-42)-OH; (SEQ ID NO: 88)[Aib², A6c⁷, Cys(Psu)³⁵]hGIP(1-42)-OH; (SEQ ID NO: 89)[Aib², A6c⁷, Cys(Psu)³⁴]hGIP(1-42)-OH; (SEQ ID NO: 93)[Aib², A6c⁷, Cys(Psu)³¹]hGIP(1-42)-OH; (SEQ ID NO: 96)(Aib², A6c⁷, Gln⁴³)hGIP(1-43)-OH; (SEQ ID NO: 97)[Aib², A6c⁷, Cys(Psu)³²]hGIP(1-42)-OH; (SEQ ID NO: 98)[Aib², A6c⁷, Cys(Psu)⁴³]hGIP(1-43)-OH; (SEQ ID NO: 102)[Aib², A6c⁷, Cys(Psu)³³]hGIP(1-42)-OH; (SEQ ID NO: 103)[Aib², A6c⁷, Cys(Psu)³⁷]hGIP(1-42)-OH; (SEQ ID NO: 112)(NMe-Tyr¹, Aib², A5c¹¹, Nle¹⁴)hGIP(1-42)-OH; or (SEQ ID NO: 118)(Aib², A5c^(11, 14), His⁴³)hGIP(1-43)-OH;

or a pharmaceutical salt thereof.
 4. A compound according to claim 2,wherein A³¹ to A⁴³ are deleted, or a pharmaceutically acceptable saltthereof.
 5. A compound consisting essentially of residues 1-30 of SEQ IDNO:1, wherein the sequence comprises an Aib substitution at position 2,and at least one additional amino acid substitution or modification atpositions 4-30 that is not the amino acid residue of the correspondingposition in native hGIP; or a pharmaceutically acceptable salt thereof.6. A compound according to claim 5 where at least one of A⁷, A¹¹, A¹³and A¹⁴ is not the amino acid residue of the corresponding position innative GIP; or a pharmaceutically acceptable salt thereof.
 7. A compoundconsisting essentially of residues 1-42 of SEQ ID NO:1, wherein thesequence further comprises an Aib substitution at position 2, and atleast one additional amino acid substitution or modification atpositions 4-42 that is not the amino acid residue of the correspondingposition in native hGIP; or a pharmaceutically acceptable salt thereof.8. A compound according to claim 7, wherein said compound is: (Aib²,A5c¹¹, Nle¹⁴)hGIP(1-42)-OH (SEQ ID NO:57); or a pharmaceutical saltthereof.
 9. A compound according to claim 1, further comprising acovalently linked PEG moiety, or a pharmaceutically acceptable saltthereof, wherein said PEG moiety is selected from the group consistingof 5K PEG, 10K PEG, 20K PEG, 30K PEG, 40K PEG, 50K PEG, and 60K PEG, toform Cys(succinimide-N-5K PEG), Cys(succinimide-N-10K PEG),Cys(succinimide-N-20K PEG), Cys(succinimide-N-30K PEG),Cys(succinimide-N-40K PEG), Cys(succinimide-N-50K PEG),Cys(succinimide-N-60K PEG), hCys(succinimide-N-5K PEG),hCys(succinimide-N-10K PEG), hCys(succinimide-N-20K PEG),hCys(succinimide-N-30K PEG), hCys(succinimide-N-40K PEG),hCys(succinimide-N-50K PEG), hCys(succinimide-N-60K PEG),Pen(succinimide-N-5K PEG), Pen(succinimide-N-10K PEG),Pen(succinimide-N-20K PEG), Pen(succinimide-N-30K PEG),Pen(succinimide-N-40K PEG), Pen(succinimide-N-50K PEG), orPen(succinimide-N-60K PEG), or a pharmaceutically acceptable saltthereof.
 10. A pharmaceutical composition comprising an effective amountof a compound of claim
 1. 11. A method for treating type 2 diabetes,comprising the step of administering to a subject in need thereof atherapeutically effective amount of a compound of claim
 1. 12. A methodof treating diabetes-related disorders, comprising the step ofadministering to a subject in need thereof a therapeutically effectiveamount of a compound claim 1, wherein said diabetes-related disorder isselected from the group consisting of hyperglycemia, hyperinsulinemia,impaired glucose tolerance, impaired fasting glucose, dyslipidemia,hypertriglyceridemia, and insulin resistance.
 13. A method ofstimulating insulin secretion in a subject in need thereof byadministering to said subject a therapeutically effective amount of acompound of claim
 1. 14. The compound according to claim 2, wherein A⁷is A5c or A6c; or a pharmaceutically acceptable salt thereof.
 15. Thecompound according to claim 2, wherein A¹⁴ is A5c, A6c, or Nle; or apharmaceutically acceptable salt thereof.
 16. The compound according toclaim 2, wherein: A⁷ is A5c or A6c; and A¹⁴ is A5c, A6c, or Nle; or apharmaceutically acceptable salt thereof.